1. Field of the Invention
The present invention is directed to compounds having specific or selective activity as agonists of RARγ retinoid receptors. More specifically, the present invention is directed to disubstituted chalcone oximes that have specific or selective activity as agonists of RARγ retinoid receptors.
2. Background Art
Compounds that have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. It is now general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors are respectively designated the RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RARα, RARβ and RARγ, in RXR the subtypes are: RXRα, RXRβ and RXRγ. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several subtypes is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids are mediated by one or more of the RAR receptor subtypes. Accordingly, among compounds having agonist-like activity at retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property.
For a general overview of the retinoid receptors see Mangelsdorf et al. (1994) The Retinoid Receptors In: The Retinoids, edited by Sporn et al. p 319-349. Raven Press, Ltd., New York. For another general overview see Dawson and William H. Okamura, Chemistry and Biology of Synthetic Retinoids, published by CRC Press Inc., 1990, pages 324-356.
Relatively recently it has been discovered that compounds which are selective or specific agonists (ligands) of RARγ retinoid receptors are capable of preventing or treating alveolar destruction in the lungs of mammals, or are capable of promoting the formation of alveoli in mammalian lungs which are deficient in adequate numbers of functional alveoli. Thus, such specific or selective agonists of RARγ retinoid receptors are useful for the prevention or treatment of emphysema and related pulmonary insufficiency diseases or conditions. See U.S. Pat. No. 6,492,414 assigned to the same assignee as the present application:
U.S. Pat. No. 6,403,810 describes vinyl compounds substituted with a thiophene group and with an indan, tetrahydrobenzofuran, tetrahydrobenzothiophene or tetrahydrobenzopyrrole group useful for treating emphysema and associated pulmonary diseases. PCT Publication WO 02/28810 A2 also discloses compounds useful for treating emphysema and associated pulmonary diseases and the general formulas provided in this disclosure include chalcone oxime compounds.
“Chalcone moiety” or “chalcone linker” and “chalcone oxime linker” are terms for describing in this application moieties that have the structure shown below
and which in the present invention covalently link two aromatic or heteroaromatic moieties. In the formula the stars indicate the carbons to which the aromatic rings are attached, respectively.
The following references disclose retinoid compounds which are disubstituted “chalcone” compounds: U.S. Pat. Nos. 6,455,701; 6,469,028; 6,225,494; 5,723,666; 5,739,338 and 5,760,276.
U.S. Pat. Nos. 5,723,666; 5,599,967; and 5,605,915 disclose retinoid compounds which include an oxime moiety.